Manganese compositions and methods for MRI

Abstract

An MRI contrast medium of improved safety and efficacy is disclosed. The composition includes a source of calcium ions and a source of manganese ions in a ratio of from 2:1 to 40:1 in a vehicle suitable for parenteral administration. A method of enhancing an MRI signal in a mammalian tissue with the foregoing composition is also provided.

We claim: 
     
       1. A diagnostic composition comprising a source of a diagnostically effective quantity of Mn++ ion, a source of Ca++ ion and a pharmaceutically acceptable carrier for parenteral administration, wherein said Ca++ ion is present in a molar ratio of from 2:1 to 40:1 with respect to said Mn++ ion. 
     
     
       2. A diagnostic composition according to claim 1 wherein said source of Mn++ is a manganese salt chosen from manganese acetate, chloride, gluconate, gluceptate, lactate and sulfate or a mixture thereof. 
     
     
       3. A diagnostic composition according to claim 2 wherein said source of Mn++ is manganese gluconate or manganese gluceptate. 
     
     
       4. A diagnostic composition according to claim 1 wherein said source of Ca++ is a calcium salt chosen from calcium acetate, chloride, gluconate, gluceptate, and lactate or a mixture thereof. 
     
     
       5. A diagnostic composition according to claim 4 wherein said source of Ca++ is calcium gluconate or calcium gluceptate. 
     
     
       6. A diagnostic composition according to claim 1 wherein said molar ratio of calcium to manganese is from 4:1 to 20:1. 
     
     
       7. A diagnostic composition according to claim 6 wherein said molar ratio of calcium to manganese is from 8:1 to 10:1. 
     
     
       8. A diagnostic composition according to claim 1 additionally comprising an antioxidant. 
     
     
       9. A diagnostic composition according to claim 8 wherein said antioxidant is ascorbate. 
     
     
       10. A diagnostic composition according to claim 1 additionally comprising a stabilizer. 
     
     
       11. A diagnostic composition according to claim 10 wherein said stabilizer is calcium saccharate or a borate complex. 
     
     
       12. A unit dosage form comprising a salt of manganese containing from 5 mg to 200 mg of manganese, a salt of calcium containing from 20 mg to 3 g of calcium, and a vehicle suitable for parenteral injection. 
     
     
       13. A unit dosage form according to claim 12 comprising from 60 mg to 1.5 g of manganese gluconate or manganese gluceptate and from 250 mg to 32 g of calcium gluconate or gluceptate. 
     
     
       14. A unit dosage form according to claim 13 in a water-for-injection vehicle adjusted to pH 6.0 to 8.2, additionally comprising calcium saccharate in an amount such that about 4% to about 8% of the calcium present in the dosage form is in the form of calcium saccharate. 
     
     
       15. A method for enhancing a magnetic resonance image of a mammalian tissue, organ or system comprising administering to a mammal a diagnostically effective amount of a source of Mn++ ion together with from 2 to 200 molar equivalents of a source of Ca++ ions. 
     
     
       16. A method according to claim 15 wherein said source of Mn++ is a manganese salt chosen from manganese acetate, chloride, gluconate, gluceptate, lactate and sulfate or a mixture thereof and said source of Ca++ is a calcium salt chosen from calcium acetate, chloride, gluconate, gluceptate, and lactate or a mixture thereof. 
     
     
       17. A method according to claim 16 wherein said source of Mn++ is manganese gluconate or manganese gluceptate and said source of Ca++ is calcium gluconate or calcium gluceptate. 
     
     
       18. A method according to claim 15 wherein the molar ratio of calcium to manganese is from 4:1 to 20:1. 
     
     
       19. A method according to claim 15 wherein the molar ratio of calcium to manganese is from 8:1 to 10:1. 
     
     
       20. A method for enhancing a magnetic resonance image of a mammalian tissue, organ or system comprising administering to a mammal from 1 μmol/kg body weight to 100 μmol/kg body weight of a source of Mn++ ion together with from 2 μmol/kg body weight to 1400 μmol/kg body weight of a source of Ca++ ions. 
     
     
       21. A method according to claim 20 wherein said source of manganese and said source of calcium are administered intravenously. 
     
     
       22. A method according to claim 21 wherein said source of manganese is administered at 2 μmol/kg body weight to 30 μmol/kg body weight and said source of calcium is administered at 4 μmol/kg body weight to 400 μmol/kg body weight. 
     
     
       23. A method according to claim 22 wherein said source of manganese is administered at 3 μmol/kg body weight to 15 μmol/kg body weight and said source of calcium is administered at 6 μmol/kg body weight to 200 μmol/kg body weight. 
     
     
       24. A method according to claim 20 wherein the tissue, organ or system is chosen from liver, kidney, pancreas, adrenal glands, heart, brain, salivary glands, gastrointestinal mucosa, uterus, the biliary system and tumor. 
     
     
       25. A method according to claim 20 wherein the tissue, organ or system is the circulatory system. 
     
     
       26. A method according to claim 20 wherein the source of Mn++ is administered separately within 30 minutes following the administration of the source of Ca++. 
     
     
       27. A method according to claim 20 wherein the source of Mn++ and the source of Ca++ are administered simultaneously.